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Cytokine Storms in COVID-19, Hemophagocytic Lymphohistiocytosis, and CAR-T Therapy
No full textImportance: Cytokine storm (CS) is a hyperinflammatory syndrome causing multiorgan dysfunction and high mortality, especially in patients with malignant hematologic neoplasms. Triggers include malignant neoplasm-associated hemophagocytic lymphohistiocytosis (MN-HLH), cytokine release syndrome from chimeric antigen receptor T-cell therapy (CAR-T CRS), and COVID-19, but the underlying mechanisms of inflammation and their impact on outcomes are poorly understood.
Objective: To delineate the inflammatory patterns characterizing different CS etiologies and their association with clinical outcomes.
Design, setting, and participants: This retrospective cohort study was conducted at the MD Anderson Cancer Center in Houston, Texas, between March 1, 2020, and November 20, 2022, using the software-as-a-service Syntropy Foundry Platform. Participants were patients with malignant hematologic neoplasms who developed CS from COVID-19 (COVID-CS), MN-HLH, or CAR-T CRS.
Exposure: Diagnostic criteria for COVID-CS were developed based on surging inflammatory markers (interleukin-6, C-reactive protein, and ferritin), while diagnosis of MN-HLH and CAR-T CRS followed established guidelines.
Main outcomes and measures: The study compared cytokine levels, clinical characteristics, and survival outcomes across the 3 cohorts and focused on inflammatory markers, survival times, and key factors associated with survival identified through univariate and multivariable analyses.
Results: A total of 671 patients met the inclusion criteria. Of those, 220 (33%) had CAR-T CRS, 227 (34%) had COVID-CS, and 224 (33%) had MN-HLH. Patients were predominantly male (435 [65%]), and 461 (69%) were White, with significant differences in median age (CAR-T CRS, 63 [IQR, 54-71] years; COVID-CS, 63 [IQR, 52-72] years; MN-HLH, 55 [IQR, 41-65] years; P \u3c .001) as well as number of admission days and underlying cancer type across cohorts. Marked variations in cytokine levels and survival outcomes were observed, with the MN-HLH cohort exhibiting the highest levels of inflammatory markers (eg, median TNF-α, 105 pg/mL [IQR, 38-201 pg/mL] for MN-HLH vs 23 pg/mL [IQR, 17-42 pg/mL] for COVID-CS) and lowest fibrinogen and albumin levels. The cohort with CAR-T CRS showed substantially longer survival times compared with the cohort with COVID-CS (hazard ratio [HR], 2.93; 95% CI, 1.95-4.41) and the cohort with MN-HLH (HR, 8.12; 95% CI, 5.51-12.00). Clustering analysis showed overlapping patterns between COVID-CS and CAR-T CRS, while MN-HLH formed a distinct cluster.
Conclusions and relevance: This study of CS syndromes found distinct immune responses within each cohort. The distinct clinical patterns and outcomes associated with different CS etiologies emphasize the importance of early diagnosis and timely intervention
Evaluating the Impact of Epic Integration and Dual Registered Nurse Check-Off on Pressure Injury Prevention Workflow Compliance
No full textBackground
Hospital-acquired pressure injuries (HAPIs), particularly sacral and heel injuries, remain a persistent challenge in critical care settings, leading to increased morbidity, mortality, and healthcare costs.
Purpose
This quality improvement project aimed to improve compliance with a pressure injury prevention (PIP) workflow by integrating a dual RN check-off system within EPIC, thereby reducing sacral and heel pressure injuries. The project sought to enhance accountability, standardize documentation, and optimize compliance with evidence-based PIP measures.
Methodology
A Plan-Do-Study-Act (PDSA) framework guided the project implementation in an oncologic intensive care unit (ICU). Key interventions included: (1) EPIC integration of a dual RN check-off system to improve accountability in pressure injury prevention measures, (2) structured nursing education sessions addressing knowledge gaps, and (3) compliance tracking through audit reports. Pressure injury incidence and compliance with documentation protocols were monitored through descriptive statistics, compliance audits, and incidence tracking.
Results
Implementation of the dual RN check-off system resulted in a 75% reduction in sacral and heel pressure injuries during the intervention period. Compliance with pressure injury prevention protocols progressively improved following educational reinforcement, system integration, and real-time feedback mechanisms.
Implications
Findings highlight the effectiveness of structured verification processes, EPIC integration, and ongoing education in improving compliance and reducing pressure injuries. Expansion to other ICU settings is feasible with strong leadership support and interdisciplinary collaboration for sustainability. Future efforts should focus on continuous education, workflow optimization, and reinforcement strategies to sustain compliance and reduce HAPIs
Serotonin Neurons Integrate GABA and Dopamine Inputs To Regulate Meal Initiation
No full textObesity is a growing global health epidemic with limited orally administered therapeutics. Serotonin (5-HT) is one neurotransmitter which remains an excellent target for new weight-loss therapies, but a gap remains in understanding the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using an optogenetic feeding paradigm, we showed that the 5-HTDRN→arcuate nucleus (ARH) circuit plays a role in meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the role of dopaminergic inputs via dopamine receptor D2 in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, for the initiation of a meal
Advancing Drug Development in Myelodysplastic Syndromes
Full text linkMyelodysplastic syndromes/neoplasms (MDSs) are heterogeneous stem cell malignancies characterized by poor prognosis and no curative therapies outside of allogeneic hematopoietic stem cell transplantation. Despite some recent approvals by the US Food and Drug Administration, (eg, luspatercept, ivosidenib, decitabine/cedazuridine, and imetelstat), there has been little progress in the development of truly transformative therapies for the treatment of patients with MDS. Challenges to advancing drug development in MDS are multifold but may be grouped into specific categories, including criteria for risk stratification and eligibility, response definitions, time-to-event end points, transfusion end points, functional assessments, and biomarker development. Strategies to address these challenges and optimize future clinical trial design for patients with MDS are presented here
Identifying and Characterizing Transition Cells in Developmental Processes from scRNA-Seq Data
No full textDuring the development of multicellular organisms, individual cells make distinct decisions about their cell types and states. Understanding the molecular mechanisms underlying cellular state transitions at different developmental stages provides deep insights into physiology, morphology and the etiology of diseases. Single-cell RNA-sequencing (scRNA-seq), which is widely used to study complex cell states and dynamic gene expression patterns, enables us to investigate molecular mechanisms of cellular state transitions. Currently, however, computational tools available for identifying cellular states and state transitions remain limited.
Although trajectory-based methods such as Monocle and Slingshot assume that state transitions generate continuous expression profiles, they cannot distinguish transition cells from stable ones. Cellular state transitions, which initiate key steps of developmental processes such as differentiation, dedifferentiation, and transdifferentiation, ultimately determine distinct cell fates. While methods like CellRank and MuTrans identify transition cells using macrostates and attractor basins, they rely on cell-cell similarity rather than intrinsic gene regulatory mechanisms. A systematic approach for distinguishing and characterizing transition cells from stable cells is still lacking.
In this dissertation, I model scRNA-seq data from developmental processes as a function of gene regulatory relations using stochastic differential equations (SDEs). Based on dynamical systems theory, I developed a statistical approach, CellTran, which leverages pairwise gene expression correlation coefficients to infer cell state transitions. I validated this method using simulation datasets generated by SERGIO and real-world mouse tissue regeneration scRNA-seq data. I also applied the analytical framework to scRNA-seq datasets from a PDAC (Pancreatic ductal adenocarcinoma) mouse model and humoral responses against SARS-CoV-2 vaccines. By identifying transition cells in pancreatic preinvasive lesions, we observe tumor heterogeneity and can predict distinct cell fate even at early stages of tumorigenesis. Additionally, characterizing transition cells after SARS-CoV-2 vaccination allows us to observe the protective effects of vaccines against severe cases. Identifying and characterizing transition cells can potentially provide valuable biomarkers for disease diagnosis, prognosis and therapeutic development
Improving the Patient Care Experience in Residential Eating Disorder Treatment: A Quality Improvement Project
No full textPurpose
The purpose of this project was to implement structured biweekly patient check-ins at a residential treatment facility for eating disorders. This project was intended to increase the patient care satisfaction scores on patient discharge surveys from under 80% to over 90%.
Background
The project was implemented at a 12-bed residential treatment facility for adolescents and adults diagnosed with eating disorders located in Cypress, Texas.
Methodology
The Baird 2007 concept of scripting during rounds was utilized as well as the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAPS) patient care experience survey questions when creating the script used during biweekly check-ins. The check-ins were recorded in an anonymous survey and compared monthly. The Institute of Healthcare Improvement’s Plan-Do-Study-Act (PDSA) cycle was utilized with a plan to meet with leadership every 2 months.
Results
After 4 months of implemented patient biweekly check-ins, the mean of patient discharge survey scores was over 90%. Only 1 PDSA cycle was completed with 6 patients completing eating disorder treatment during the period of project implementation.
Implications
The implementation of regular patient check-ins may lead to improvement in the overall patient care experience at a residential treatment care facility where rounds are not a part of the schedule. The sustainability of this project is dependent on leadership’s willingness to train staff on scripted patient check-ins
Investigating metabolic and mitochondrial adaptations triggered by blood flow during the endothelial-to-hematopoietic transition
No full textHematopoietic stem cell (HSC) transplant is the standard of care for many hematologic diseases. However, many patients cannot benefit from this potentially curative treatment because they cannot find a suitable donor, contributing to a high level of unmet need. Recently, bona fide HSCs capable of robust engraftment and differentiation have been generated from iPSCs utilizing wall shear stress (WSS) to help promote HSC generation. However, the mechanisms through which WSS regulates hematopoiesis remain poorly understood. Scientists, therefore, continue to look for the mechanotransduction pathways that promote hematopoiesis, and key answers may lie in examining the role of extrinsic factors that regulate hematopoiesis in the developing embryo.
We show that the physical forces associated with blood flow are critical for regulating metabolic shifts necessary for the specification of HSCs emerging from arterial vessels during embryogenesis. Mutant embryos lacking a heartbeat fail to produce HSCs and only have hematopoietic precursors with immature mitochondria containing fewer cristae, as determined by electron microscopy. Force generated by blood flow stimulates mitochondrial protein translation, cristae formation, increased mitochondrial membrane potential, and oxidative phosphorylation. These adaptations can be mimicked ex vivo by exposing cultured hematopoietic precursors to force, resulting in increased mitochondrial activity with improved transplantation performance. Single-cell transcriptome and protein analyses indicate that force-responsive PI3K-Akt signaling regulates mTORC1 effectors S6K and 4E-BP1 to promote translation of mitochondrial ribosomes and electron transport chain proteins.
Our work exposes an overlooked role of force in the maturation of mitochondrial machinery essential for HSC emergence and population of the blood system. Our study provides clues to essential flow-sensitive molecular mechanisms that can be leveraged for future HSC engineering
HER2-Selective Tyrosine Kinase Inhibitor, Zongertinib (BI 1810631), in Patients With Advanced/Metastatic Solid Tumors With HER2 Alterations: A Phase Ia Dose-Escalation Study
No full textPurpose: Human epidermal growth factor receptor 2 (HER2) alterations occur in many solid cancers, including non-small cell lung cancer (NSCLC). Beamion LUNG-1 (ClinicalTrials.gov identifier: NCT04886804) is assessing the safety/efficacy of zongertinib (BI 1810631), a novel HER2-selective tyrosine kinase inhibitor that spares epidermal growth factor receptor, in patients with HER2-altered solid tumors.
Materials and methods: Beamion LUNG-1 is an ongoing multicenter, multicohort phase Ia/Ib trial. Phase Ia assessed zongertinib administered twice a day (15-150 mg) or once daily (60-360 mg) in pretreated patients with various tumors, including NSCLC. Primary end points were maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs); tumor response was a secondary end point.
Results: As of May 23, 2024, 105 patients were treated. Two DLTs occurred during the MTD evaluation period; MTD was not reached (NR). The recommended doses for expansion were 120 mg once daily and 240 mg once daily. Treatment-related adverse events (TRAEs; any/grade ≥3) occurred in 82%/10% of patients. The most common TRAEs (any/grade ≥3) included diarrhea (50%/1%), rash (16%/2%), anemia (10%/0%), decreased appetite (10%/1%), and increased alanine transaminase (10%/4%). The confirmed investigator-assessed overall response rate (ORR) across all doses/tumors was 30% (95% CI, 23 to 40); median duration of response was 12.7 months (95% CI, 6.9 to NR). In 54 patients with NSCLC, confirmed ORR was 35% (95% CI, 24 to 49). Activity was observed in patients with A775_G776insYVMA (ORR, 38%) and those who had received previous HER2-directed therapy (ORR, 28%). In patients with NSCLC receiving zongertinib once daily, median progression-free survival was 17.2 months (95% CI, 8.3 to NR).
Conclusion: Zongertinib had a manageable safety profile and demonstrated preliminary antitumor activity in patients with HER2-altered tumors, including those with HER2-mutant NSCLC
Frailty and Sleep in Adult Survivors of Childhood Cancer: A Childhood Cancer Survivor Study Report
No full textBackground: Young adult survivors of childhood cancer exhibit rates of frailty similar to adults several decades older without a cancer history. Frailty has been associated with sleep disturbances in non-cancer populations, but the relationship has not been examined in childhood cancer survivors who are known to exhibit elevated rates of sleep problems.
Aims: Examine associations between frailty and poor sleep quality in long-term survivors of childhood cancer.
Methods: This study utilized data from 9044 participants (\u3e 5 years from diagnosis, Mage = 40.8 years [SD = 9.5]) in the Childhood Cancer Survivor Study. Survivors\u27 frailty status, chronic health conditions (CHC), health behaviors, mental health, and pain were collected in 2014-2016, and self-reported sleep quality in 2017-2019. Multivariable logistic regression models examined frailty status as a predictor of clinically significant poor sleep. All models were adjusted for age at diagnosis, age at survey, sex, race/ethnicity, smoking, risky/heavy alcohol use, and physical inactivity. Separate models included treatment-related variables, CHC burden (number/severity), and emotional health/pain as co-variates.
Results: Frail survivors had 6-fold (95% CI 4.48-7.96) increased odds of future poor sleep quality. Little attenuation of this association was observed when accounting for cancer diagnosis (Odds Ratio [OR] 5.80, 95% CI 4.47-7.52), treatment exposures (OR 5.80, 95% CI 4.43-7.71), or chronic health condition burden (OR 5.12, 95% CI 3.98-6.59), but adjustment for emotional health/pain (OR 2.88, 95% CI 2.18-3.82) attenuated the association appreciably.
Conclusions: Frail childhood cancer survivors have a higher prevalence of clinically significant poor sleep quality. Addressing poor physiologic reserve may impact sleep in frail childhood cancer survivors
Differential progression of pancreatic premalignancy in geographically distant murine transgenic cohorts uncovers key role of microbial metabolites
No full textCancer is a leading cause of death worldwide. Despite recent advances in diagnostic and therapeutic modalities, pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that remains highly lethal. Efforts have been made to increase the understanding of the underlying mechanisms driving early stages of tumor development, when the cancer is most susceptible to intervention. To this end, genetically engineered mouse models (GEMMs) have been developed with the mutations most commonly seen in the patient population. Expression of these mutations in select cellular compartments has resulted in the ability to recapitulate characteristics of human pancreatic cancer such as the development of precursor lesions, metastatic activity, and cytokine signaling. These models represent convenient and cost-effective tools to investigate various aspects of pancreatic cancer. The utility of these genetic models, however, may be stymied by inherent variation between research institutions, including commensal bacteria present at individual facilities that has been shown to influence the host immune system. The microbiota, or the community of microbes, present in the gut has gained recent attention for the pivotal role it plays in myriad aspects of host physiology. The relationship between microbes and cancer is complex. Recent studies have shown that PDAC patients harbor distinct gut microbiomes relative to healthy patients, and that transplantation of gut microbes from patients into mice can differentially alter the rate of tumor progression in murine models of PDAC. The potential mere association between pancreatic cancer and microbiome changes vs the potential role of microbiome in cancer initiation remains not fully elucidated.
To this end, we serendipitously identified two cohorts of mice housed at geographically distinct vivaria that exhibited significantly different rates of pancreatic premalignancy despite possessing a shared lineage. After ruling out potential differences in food and water sources as well as handling protocols, we examined composition of the gut microbiomes in both cohorts. These analyses revealed that in addition to possessing significantly different rates of tumorigenesis, mice harbor distinct gut microbiomes at the respective geographically distant vivarium. Fecal microbiota transplantation (FMT) experiments consist of transplanting fecal bacteria and other microbes from a donor directly into the gastrointestinal tract of the recipient and have been used clinically to treat conditions as recurrent Clostridioides difficile infections and inflammatory bowel disease. We assessed the ability of FMT to influence the rate of pancreatic tumorigenesis in mice, which significantly accelerated the rate of premalignancy in the mice housed in the vivaria characterized by slow phenotype.
To interrogate the effect of downstream effects elicited by differences in the gut microbiome, we interrogated the metabolome of mice housed at the separate institutions. These analyses identified an abundance of succinic acid in the plasma and pancreata of mice displaying the accelerated phenotype. We utilized an independent transgenic mouse model in which PDAC driver mutations are expressed pancreas-wide, which developed a wide array of pancreatic dysplasia. These data suggest that this microbially dependent protective effect is specific to the cells of acinar origin. Furthermore, this independent mouse model demonstrated an increase in plasma levels of succinic acid in relation to pancreatic dysplasia, validating our identification of succinic acid as a metabolite of interest.
To better understand the mechanisms by which bacterially mediated succinic acid may promote the progression of pancreatic premalignancy, we examined the rate of transformation of pancreatic explanted acinar cells to ductal-like structures. Following the addition of succinic acid or succinic acid producing bacteria, we observed a significant increase in morphological transformation. This increase in transformation was also reflected by an increased expression of ductal genes. Due to previous reports that abundant succinic acid stabilizes HIF1α, we sought to determine the role of HIF1α signaling in our model. We observed that pre-treatment of acinar explant cells with a commercially available HIF1α inhibitor abrogated the pro-tumorigenic effects of succinic acid and succinic acid producing bacteria. Furthermore, we identified increased expression of HIF1α and target genes in cells exposed to succinic acid in vitro.
In addition to microbially mediated mechanisms that promote the early development of pancreatic cancer, we also investigated immune signaling capable of mediating tumorigenesis. By generating transgenic animals lacking IL-17 receptor A (IL-17RA) in epithelial compartments, we observed delayed initiation and progression of premalignant lesions. We identified that B7-H4, a known inhibitor of T cell activation was highly upregulated via IL-17 during the early stages of tumorigenesis. In addition to increased expression of B7-H4, we identified increased levels of T cell exhaustion marker, Eomes. Histological staining confirmed increased expression of Eomes. Taken together these data suggest that within the pancreatic epithelium, IL-17 signaling regulates B7-H4 which can promote T cells exhaustion.
In this dissertation we provide novel insights into the mechanisms, both microbial and immune, that drive the early development of pancreatic cancer and identify innovative opportunities for potential cancer interception and therapy